Aminoalkylindoles, their production, and pharmaceutical preparations based thereon
This is a division of application Ser. No. 370,509, filed June 23, 1989, now U.S. Pat. No. 4,943,572. 
    
    
     CROSS-REFERENCE TO RELATED APPLICATIONS 
     Indole derivatives are disclosed in applicants&#39; earlier U.S. patent application Ser. No. 07/330,047, filed Mar. 29, 1989, now abandoned based on a series of parent applications and claiming priority of German Application No. P 38 15 993.1, filed Apr. 13, 1981. 
     BACKGROUND OF THE INVENTION 
     The present invention relates to aminoalkylindoles, processes for their production, and pharmaceutical preparations containing same. 
     SUMMARY OF THE INVENTION 
     Objects of this invention are to provide novel chemical compounds, processes of making compounds, pharmaceutical preparations, and methods of administering such preparations. 
     Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art. 
     To attain such objects, there are provided aminoalkylindoles of Formula I ##STR3## wherein R 1  is hydrogen, hydroxyl, or an alkanoyloxy group containing 1-10 carbon atoms, 
     R 2  is a hydroxyl or an alkanoyloxy group containing 1-10 carbon atoms, 
     R 3  is hydrogen or methyl, 
     R 4 , R 5 , being the same or different, represent hydrogen, alkyl of 1-10 carbon atoms, aralkyl of 7-10 carbon atoms, or cycloalkyl of 3-7 carbon atoms, or 
     R 4 , R 5 , with the inclusion of a single nitrogen atom or with the inclusion of a nitrogen and an oxygen atom or with the inclusion of two nitrogen atoms as heteroatoms, form a 5- or 6-membered heterocyclic ring, and 
     n is an integer in the range of 4-15, inclusive, 
     and the salts thereof are preferably physiologically acceptable salts of these compounds with acids. 
     Suitable as R 1  and R 2  alkanoyloxy groups are radicals of organic carboxylic acids containing 1-10 carbon atoms, which radicals can be saturated or unsaturated. They are derived from aliphatic, cycloaliphatic, aliphatic cycloaliphatic, cycloaliphatic aliphatic, and aromatic monocarboxylic acids. When a cyclic acid, the number of carbon atoms in the ring varies from 3 to 7, inclusive. The alkanoyloxy groups of acetic, propionic, butyric, isobutyric, pivalic, caproic, acrylic, crotonic, heptanoic, caprylic, pelargonic, decanoic, 3-cyclopentylpropionic, and benzoic acid are preferred as radicals R 1  and R 2 . 
     The radical R 1  can be in the positions 4, 5, 6, or 7 of the indole ring system, with the 5-position being especially suitable. 
     The radical R 2  can be in the positions 2, 3, or 4 on the phenyl ring, when the position is the point of linkage to the 2-position of the indole system. Such compounds are especially pharmaceutically active when the radical R 2  is in the 4-position (para position). 
     Alkyl groups containing 1-10 carbon atoms and cycloalkyl groups of 3-7 carbon atoms are suitable as the R 4  and R 5  radicals. 
     Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decanyl and isomers thereof are suitable as alkyl groups, and cyclopentyl and cyclohexyl are especially suitable as cycloalkyl groups. 
     Benzyl is a particular example of an aralkyl group represented by the R 4  and/or R 5  radicals. 
     The radicals R 4  and R 5  can be the same or different or can be components of a common ring. With the presence of a ring, the latter can contain, in addition to the nitrogen atom, an oxygen atom and a second nitrogen atom. 
     Particularly suitable as R 4  and R 5  radicals are the combination of hydrogen/methyl (derived from methylamino), hydrogen/hydrogen (derived from amino), and methyl/methyl (derived from dimethylamino), as well as the (CH 2 ) 4  radical (derived from pyrrolidino), the (CH 2 ) 5  radical (derived from piperidino), the (CH 2 ) 2  --O--(CH 2 ) 2  radical (derived from morpholino), and the (CH 2 ) 2  --NH--(CH 2 ) 2  radical (derived from piperazino). 
     The invention also relates to salts of compounds of Formula I. These salts can be both salts or inorganic and of organic acids. Especially suitable are the physiologically compatible salts, such as, for example, hydrochlorides, hydrobromides, acetates, malonates, and citrates. 
     The invention further relates to processes for the production of aminoalkylindoles of general Formula I. In this case, a compound of Formula IIa ##STR4## or of Formula IIb ##STR5## wherein R 3 , R 4 , R 5 , and n have the same meaning specified in Formula I, 
     R 6  is hydrogen or alkoxy containing 1-4 carbon atoms, and 
     R 7  is alkoxy containing 1-4 carbon atoms 
     is reacted under the conditions of an ether cleavage to a compound of Formula Ia ##STR6## 
     Alternatively, a compound of Formula IIIb ##STR7## wherein R 8  is hydrogen or hydroxyl, the carbonyl function of the compound of Formula IIIb is completely reduced, and then the free aromatic hydroxyl group(s) is/are converted into an alkanoyloxy group having 1-10 carbon atoms. 
     A compound of Formula I is optionally converted with an organic or inorganic acid into the corresponding salt. 
     As alkoxy groups of the radicals R 6  and R 7 , suitable are those having 1-4 carbon atoms, such as, for example, the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertbutoxy groups. 
     Those compounds of compound II, in which R 6  and R 7  represent alkoxy groups having 1-4 carbon atoms can be converted into the corresponding hydroxy groups of Formula I by ether cleavage. The ether cleavage takes place with or without a solvent. Boron tribromide, boron trifluoride, aluminum trichloride, silicon tetrachloride, aluminum tribromide, sodium methylthiolate, and trimthylsilyl iodide are suitable reagents for the ether cleavage. The reaction is generally performed at temperatures between -70° and 200° C. Inert solvents are suitable as solvents for this ether cleavage, for example, aliphatic halogenated hydrocarbons, e.g., methylene chloride; aromatic hydrocarbons, e.g., benzene, toluene, and xylene; halogenated aromatic hydrocarbons, e.g., chlorobenzene, dichlorobenzene; and dimethylformamide, as well as acetonitrile. Aliphatic ethers with alkyl radicals from 1-6 carbon atoms are also suitable. 
     Alternatively, the ether cleavage can also take place with the use of concentrated hydroiodic acid, pyridine hydrochloride, hydrobromic acid, and methyl magnesium iodide at temperatures between 20° and 250° C. 
     The processes usually used in chemistry for esterification are suitable for the optional subsequent esterification of the phenolic hydroxyl groups. For example, esterification can be conducted with a carboxylic acid or a carboxylic acid anhydride in the presence of strong acids, such as, for example, trifluoroacetic acid, perchloric acid, or p-toluenesulfonic acid, at room temperature, or at a somewhat elevated temperature. Similarly, the esterification can be conducted with a carboxylic acid anhydride in the presence of a tertiary amine at about 20°-80° C. 
     If pyridine and 4-dimethylaminopyridine are used together as tertiary amines, the esterification preferably can be performed at room temperature. 
     Any subsequent salt formation reaction is conducted under conventional conditions. 
     It has been found that compounds of Formula I and compounds of Formula IIIb have strongly anti-estrogenic properties. 
     Compounds with anti-estrogenic properties, i.e., materials which exhibit inhibitory activity against estrogens, have already been described in the literature. 
     Tamoxifen, for example, can be mentioned as an anti-estrogen (Eur.J. Cancer Clin. Oncol 1985, 21, 985, and J. S. Patterson, &#34;10 Years of Tamoxifen in Breast Cancer,&#34; in Hormonal Manipulation of Cancer: Peptides, Growth Factors and New (Anti) Steroidal Agents (Raven Press: New York, 1987). 
     Steroidal anti-estrogens are described in European Patent Application No. 0138 504. Other anti-estrogens, which, like the present invention, relate to indole derivatives, have already been described in German Patent Specification No. 32 32 968, in J.Med.Chem. 1983, 26, 113; J.Med.Chem., 1984, 27, 1439; Eur.J. Cancer Clin. Oncol. 1985, 21, 531; and Cancer Treatment RevieWs 1984, 11, 147. Hydroxylated 2-phenylindoles, which are present in the form of diamine platinum (II) complex compounds, are named in German Laid-Open Specification No. 37 30 746. 
     A disadvantage of the previously known anti-estrogens is that they also have a more or less strongly pronounced estrogenic activity, which is considered to be undesirable. 
     In contradistinction, the compounds of Formula I and Formula IIIb of the present invention exhibit strong anti-estrogenic activity, with only minimal residual estrogen activity. 
     The compounds of Formula I have a marked affinity for the estradiol receptor and competitively displace  3  H-17β estradiol from the receptor. 
     In vivo, they exhibit strong anti-estrogenic effects on the mouse uterus and inhibit the estrogen-stimulated uterus growth up to 100 percent. Conversely, estrogen activity cannot be detected or can be detected only to a small extent in these tests. Of particular important is that these compounds have an inhibiting effect on the growth of hormone-dependent tumor cells, especially on the growth of estrogen-dependent human breast tumor cells (MCF-7). 
     Thus, the compounds according to the invention are suitable for therapy of estrogen-dependent diseases for example, anovular infertility, prostatic hyperplasia, breast cancer, endometrium cancer, and melanoma. 
     The following pharmacological tests show the action of the compounds according to the invention. 
     Table 1 shows an overall view of the tested compounds of Formula I and their relative binding affinity (RBA*) for the estrogen receptor from calf uterus, relative to 17 β estradiol=100. 
     The test protocol is described in Cancer Treatment Reviews 1984, 11, 147. 
     From Table 1 it can be seen that compounds 2, 3, 6, and 8 exhibit the greatest affinity in comparison with estradiol. In this tested series, compound 7 exhibited the least affinity for the estrogen receptor. 
     
                       TABLE 1                                                     
______________________________________                                    
Tested compounds of formula I and their relative binding                  
affinities for the estrogen receptor                                      
 ##STR8##                                                                 
Compound n      R.sub.3 R.sub.4  R.sub.5                                  
                                        RBA*                              
______________________________________                                    
1        4      CH.sub.3                                                  
                        (CH.sub.2).sub.4                                  
                                      3.6                                 
2        6      CH.sub.3                                                  
                        H        H      25                                
3        6      CH.sub.3                                                  
                        CH.sub.3 H      27                                
4        6      CH.sub.3                                                  
                        CH.sub.3 CH.sub.3                                 
                                        12                                
5        6      H       (CH.sub.2).sub.4                                  
                                      2.3                                 
6        6      CH.sub.3                                                  
                        (CH.sub.2).sub.4                                  
                                      21                                  
7        6      H       (CH.sub.2).sub.5                                  
                                      1.3                                 
8        6      CH.sub.3                                                  
                        (CH.sub.2).sub.5                                  
                                      23                                  
9        8      CH.sub.3                                                  
                        (CH.sub.2).sub.4                                  
                                      7.6                                 
10       6      CH.sub.3                                                  
                        (CH.sub.2).sub.2OCH.sub.2).sub.2                  
                                      10                                  
11       6      CH.sub.3                                                  
                        C.sub.2 H.sub.5                                   
                                 C.sub.2 H.sub.5                          
                                        14                                
12       6      CH.sub.3                                                  
                        CH.sub.2 C.sub.6 H.sub.5                          
                                 H      15                                
______________________________________                                    
 *Relative binding affinities for the estrogen receptor from calf uterus, 
 relative to 17 beta estradiol = 100                                      
 
    
     Table 2 shows the estrogen and anti-estrogen activities of compounds 1, 2, 3, and 6, as well as 10, 11, and 12. These activities were found in an in vivo test on the infantile mouse. This test is fully described in Cancer Treatment Reviews 1984, 11, 147, and J.Med.Chem., 1984, 27, 1439. From Table 2, it can be seen that all tabulated compounds exhibit a strong to very strong estrogen antagonistic effect. An estrogen intrinsic activity is hardly detectable in all the tested derivatives, with the exception of compound 3, 11, and 12 at the highest tabulated dosages. 
     
                                           TABLE 2                                 
__________________________________________________________________________
Uterotrophic and antiuterotrophic action on infantile mouse               
__________________________________________________________________________
           Uterotrophic Test                                              
                        Antiuterotrophic Test                             
Cmpd Dose (ug)                                                            
           Rel. uterus wgt                                                
                        Rel. uterus wgt                                   
                                   Inhib. (%)                             
__________________________________________________________________________
Control     7.7 ± 2.5                                                  
1    1      7.6 ± 2.8                                                  
                        43.7 ± 8.2                                     
                                   5                                      
     5      8.0 ± 3.1                                                  
                         47.6 ± 10.5                                   
     25     6.4 ± 1.1                                                  
                        16.2 ± 4.6                                     
                                   78                                     
     125    6.4 ± 1.3                                                  
                        25.5 ± 7.9                                     
                                   53                                     
Estrone                                                                   
     0.4   45.8 ± 6.2                                                  
Control    15.9 ± 3.6                                                  
2    1     10.9 ± 4.7                                                  
     5     12.0 ± 2.2                                                  
                        30.0 ± 9.1                                     
                                   68                                     
     25    12.4 ± 2.7                                                  
                        15.1 ± 1.2                                     
                                   102                                    
     125   16.9 ± 2.7                                                  
                        16.2 ± 2.7                                     
                                   99                                     
3    1     14.2 ± 3.1                                                  
     5     22.8 ± 8.6                                                  
                        38.1 ± 8.2                                     
                                   49                                     
     25                 41.0 ± 8.5                                     
                                   43                                     
     125   34.0 ± 6.3                                                  
                        33.8 ± 2.4                                     
                                   59                                     
Estrone                                                                   
     0.4    59.8 ± 20.0                                                
Control    15.5 ± 2.9                                                  
6    1     12.5 ± 1.7                                                  
                        45.8 ± 3.2                                     
                                   20                                     
     5      9.0 ± 1.8                                                  
                        15.4 ± 1.7                                     
                                   100                                    
     25    13.9 ± 2.8                                                  
                        14.4 ± 2.2                                     
                                   103                                    
     125                 8.9 ± 1.6                                     
                                   117                                    
Estrone                                                                   
     0.4   53.4 ± 3.6                                                  
Control    11.5 ± 3.6                                                  
6    1                  48.3 ± 7.2                                     
     5                  20.1 ± 7.3                                     
                                   73                                     
     25                 12.6 ± 1.9                                     
                                   97                                     
     50     8.2 ± 1.8                                                  
     250   12.7 ± 2.7                                                  
Estrone                                                                   
     0.4   43.0 ± 7.2                                                  
Control    18.8 ± 9.6                                                  
                        18.8 ± 9.6                                     
10   1     21.2 ± 3.9                                                  
     5     19.5 ± 6.9                                                  
                    5   51.2 ± 7.5                                     
                                   8                                      
     25     21.8 ± 11.3                                                
                    25  47.7 ± 8.4                                     
                                   18                                     
     125   17.4 ± 1.7                                                  
                    125 18.0 ± 4.8                                     
                                   102                                    
Estrone                                                                   
     0.4    54.2 ± 12.1                                                
                    0.4  54.2 ± 12.1                                   
__________________________________________________________________________
     Dose           Dose                                                  
     ug/animal                                                            
            Action  ug/animal                                             
                           Action  Inhib. (%)                             
__________________________________________________________________________
Control     25.4 ± 14.5 25.4 ± 14.5                                 
11   5      24.8 ± 11.7                                                
                    5      51.3 ± 4.9                                  
                                   11                                     
     25     14.7 ± 4.3                                                 
                    25     52.1 ± 8.9                                  
                                   8                                      
     125    19.8 ± 3.3                                                 
                    125    40.0 ± 4.7                                  
                                   50                                     
     625    36.4 ± 17.6                                                
                    625    43.7 ± 7.4                                  
                                   37                                     
Estrone                                                                   
     0.4    54.6 ± 6.5                                                 
                    0.4    54.6 ± 6.5                                  
Control     18.2 ± 5.5  18.2 ± 5.5                                  
12   5      17.8 ± 4.6                                                 
                    5      53.2 ± 9.0                                  
                                   25                                     
     25     23.6 ± 2.5                                                 
                    25     44.6 ± 7.1                                  
                                   43                                     
     125    34.0 ± 7.2                                                 
                    125    40.8 ± 8.7                                  
                                   51                                     
                    625    41.8 ± 7.4                                  
                                   49                                     
Estrone                                                                   
     0.4    64.7 ± 8.7                                                 
                    0.4    64.7 ± 8.7                                  
__________________________________________________________________________
 
    
     Table 3 shows the results of research on the cytostatic activity of compounds 1 and 6 in comparison with tamoxifen. 
     On the hormone-sensitive human MCF-7 breast cells, a strong inhibition of the cell growth, determined by cell count and [ 3  H] thymidine incorporation, was found in the DNA. With concentrations of 10 -7  M, a significant lowering of the cell count and of the thymidine incorporation was found six days after incubation. Under the same conditions, tamoxifen exhibited no significant effect. 
     The test protocol for the research is fully described in Eur.J. Cancer Clin. Oncol. 1985, 21, 531. 
     
                       TABLE 3                                                     
______________________________________                                    
Action of 1 and 6 on the growth of hormone-dependent                      
human MCF-7 breast cancer cells                                           
                               [.sup.3 H] Thymidine                       
          Concn.     Cell Count                                           
                               incorporation                              
Cmpd.     (M)        (% T/C)   (% T/C)                                    
______________________________________                                    
1         1 × 10.sup.-7                                             
                     106       67                                         
          5 × 10.sup.-7                                             
                     84        76                                         
          1 × 10.sup.-6                                             
                     94        85                                         
          5 × 10.sup.-6                                             
                     62        74                                         
6         1 × 10.sup.-7                                             
                     65        32                                         
          5 × 10.sup.-7                                             
                     49        32                                         
          1 × 10.sup.-6                                             
                     24        22                                         
          5 × 10.sup.-6                                             
                     12        3                                          
8         1 × 10.sup.-7                                             
                     48                                                   
          1 × 10.sup.-6                                             
                     44                                                   
          1 × 10.sup.-5                                             
                     38                                                   
10        1 × 10.sup.-7                                             
                     75                                                   
          1 × 10.sup.-6                                             
                     52                                                   
          1 × 10.sup.-5                                             
                     36                                                   
12        1 × 10.sup.-7                                             
                     47                                                   
          1 × 10.sup.-6                                             
                     46                                                   
          1 × 10.sup.-5                                             
                     41                                                   
Tamoxifen 1 × 10.sup.- 7                                            
                     77        71                                         
          1 × 10.sup.-6                                             
                     27        27                                         
______________________________________                                    
 
    
     Tables 4, 5, and 6 show, analogously to Tables 1, 2, and 3, the corresponding data for the tested 1-carbamoylalkyl-2-phenylindoles of general Formula IIIb. 
     As can be seen from Table 5, these compounds not only exhibit marked anti-estrogenity, but at high dosages also have a significant estrogen activity. 
     
                       TABLE 4                                                     
______________________________________                                    
Tested 1-carbamoylalkyl-2-phenylindoles of                                
General Formula IIIb and Their Formula IIIb                               
and Their Relative Binding Affinities for                                 
the Estrogen Receptor                                                     
 ##STR9##                                                                 
Compound  R.sub.4       R.sub.5     RBA                                   
______________________________________                                    
16        (CH.sub.2).sub.4       7                                        
17        (CH.sub.2).sub.4      19                                        
18        (CH.sub.2).sub.2O(CH.sub.2).sub.2                               
                                26                                        
19        C.sub.2 H.sub.5                                                 
                        C.sub.2 H.sub.5                                   
                                    15                                    
20        CH.sub.2 C.sub.6 H.sub.5                                        
                        H           12                                    
______________________________________                                    
 
    
     
                                           TABLE 5                                 
__________________________________________________________________________
Uterotrophic and antiuterotrophic action of 1-carbamoylalkyl-2-           
phenylindoles of general formula IIIb on infanile mouse                   
       Uterotrophic Test                                                  
                    Antiuterotrophic Test                                 
       Dose:        Dose         Inhib.                                   
Compound                                                                  
       ug/animal                                                          
             Action ug/animal                                             
                          Action (%)                                      
__________________________________________________________________________
Control      21.9 ± 2.7                                                
                          21.9 ± 2.7                                   
16     5     18.2 ± 2.3                                                
                    5     47.5 ± 10.9                                  
                                 10                                       
       25    16.5 ± 2.4                                                
                    25    42.0 ± 7.0                                   
                                 29                                       
       125   17.7 ± 0.9                                                
                    125   35.2 ± 5.5                                   
                                 53                                       
       625   35.3 ± 10.7                                               
                    625   40.7 ± 3.9                                   
                                 44                                       
Estrone                                                                   
       0.4   50.2 ± 3.1                                                
                    0.4   50.2 ± 3.1                                   
Control      14.4 ± 2.5                                                
                          14.4 ± 2.5                                   
17     1     23.8 ± 2.8                                                
       5     17.7 ± 3.2                                                
                    5     48.7 ± 9.1                                   
                                 6                                        
       25    16.3 ± 3.0                                                
                    25    42.9 ± 4.7                                   
                                 22                                       
       125   18.6 ± 2.5                                                
                    125   29.5 ± 2.7                                   
                                 59                                       
Estrone                                                                   
       0.4   50.8 ± 7.3                                                
                    0.4   50.8 ± 7.3                                   
Control      18.8 ± 9.6                                                
                          18.8 ± 9.6                                   
18     1     20.2 ± 3.4                                                
       5     22.0 ± 5.6                                                
                    5     53.5 ± 8.7                                   
       25    21.2 ± 4.6                                                
                    25    52.8 ± 7.4                                   
       125   43.0 ± 8.2                                                
                    125   39.8 ± 18.1                                  
                                 41                                       
Estrone                                                                   
       0.4   54.2 ± 12.1                                               
                    0.4   54.2 ± 12.1                                  
Control                                                                   
19     5     18.4 ± 3.2                                                
                    5     50.9 ± 8.2                                   
                                 13                                       
       25    17.9 ± 2.0                                                
                    25    50.9 ± 4.8                                   
                                 13                                       
       125   17.6 ± 2.6                                                
                    125   44.5 ± 6.2                                   
                                 34                                       
       625   32.7 ± 6.5                                                
                    625   35.3 ± 6.1                                   
                                 66                                       
Estrone                                                                   
       0.4   54.6 ± 6.5                                                
                    0.4   54.6 ± 6.5                                   
Control      15.6 ± 5.8                                                
                          15.6 ± 5.8                                   
20     5     16.5 ± 3.6                                                
                    5     50.7 ± 5.0                                   
       25    20.9 ± 6.5                                                
                    25    46.9 ± 7.7                                   
                                 12                                       
       125   16.7 ± 3.9                                                
                    125   50.3 ± 4.6                                   
       625   19.9 ± 4.1                                                
                    625   59.5 ± 12.4                                  
                                 -23                                      
Estrone                                                                   
       0.4   51.2 ± 5.9                                                
                    0.4   51.2 ± 5.9                                   
__________________________________________________________________________
 
    
     
                       TABLE 6                                                     
______________________________________                                    
Action of 1-carbamoylalkyl-2-phenylindoles of general formula             
IIIb on the growth of hormone-dependent human MCF-7                       
breast cancer cells                                                       
Compound  Concentration (M):                                              
                        Cell Count (% T/C)                                
______________________________________                                    
16        1 · 10.sup.-7                                          
                        57.2 ± 4.4                                     
          5 · 10.sup.-7                                          
                        48.2 ± 5.4                                     
          1 · 10.sup.-6                                          
                        47.1 ± 3.7                                     
          5 · 10.sup.-6                                          
                        44.0 ± 3.6                                     
          1 · 10.sup.-5                                          
                        42.1 ± 4.0                                     
17        1 · 10.sup.-7                                          
                         89.0 ± 10.8                                   
          5 · 10.sup.-7                                          
                         95.5 ± 10.2                                   
          1 · 10.sup.-6                                          
                        96.0 ± 7.7                                     
          5 · 10.sup.-6                                          
                        99.6 ± 7.6                                     
          1 · 10.sup.-5                                          
                        86.5 ± 8.3                                     
18        1 · 10.sup.-7                                          
                        57.5 ± 6.8                                     
          5 · 10.sup.-7                                          
                        58.1 ± 6.7                                     
          1 · 10.sup.-6                                          
                        56.4 ± 5.2                                     
          5 · 10.sup.-6                                          
                        42.4 ± 3.7                                     
          1 · 10.sup.-5                                          
                        33.3 ± 2.8                                     
19        1 · 10.sup.-7                                          
                        59.7 ± 6.1                                     
          5 · 10.sup.-7                                          
                        60.1 ± 3.8                                     
          1 · 10.sup.-6                                          
                        61.4 ± 4.4                                     
          5 · 10.sup.-6                                          
                        56.2 ± 4.5                                     
          1 · 10.sup.-5                                          
                        44.9 ± 3.7                                     
20        1 · 10.sup.-7                                          
                        58.3 ± 4.9                                     
          5 · 10.sup.-7                                          
                        47.9 ± 3.0                                     
          1 · 10.sup.-6                                          
                        46.8 ± 4.2                                     
          5 · 10.sup.-6                                          
                        36.6 ± 2.5                                     
          1 · 10.sup.-5                                          
                        26.8 ± 4.2                                     
______________________________________                                    
 
    
     The invention also relates to pharmaceutical preparations which contain at least one compound of general Formulas I or IIIb, as well as their salts, and the use of these compounds for treatment of estrogen-dependent diseases and tumors. 
     The compounds according to the invention are suitable for production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as an active ingredient one or more of the compounds according to the invention, optionally in mixture with other pharmacologically or pharmaceutically active materials. The production of the pharmaceutical agents takes place in a known way, and the known and usual pharmaceutical auxiliary agents, as well as other usual vehicles and diluents, can be used. 
     Suitable as such vehicles and auxiliary agents are, for example, those that are recommended or indicated in the following literature passages as auxiliary agents for pharmacy, cosmetics, and related fields: Ullmans Encyklopaedie der technischen Chemie [Ullman&#39;s Encyclopedia of Industrial Chemistry], Vol. 4 (1953), pp. 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), p. 918 ff.; H.v. Czetsch-Lindewald, Hilfsstoffe fuer Pharmazie und angrenzende Gebiete [Auxiliary Agents for Pharmacy and Related Fields], Pharm. Ind., No. 2, 1961, p. 72 ff.; Dr. H. P. Fiedler, Lexikon der Hilfstoffe fuer Pharmazie, Kosmetik und angrenzende Gebiete [Lexicon of Auxiliary Agents for Pharmacy, Cosmetics and Related Fields], Cantor KG. Aulendorf in Wuerttemberg 1971. 
     The compounds can be administered orally or parenterally, e.g., intraperitoneally, intramuscularly, subcutaneously, or percutaneously. The compounds can also be implanted in the tissue. The amount of the compound to be administered fluctuates within a wide range. As a function of the condition to be treated and the type of administration, the amount of administered compound can generally be 0.01-100 mg/kg of body weight, preferably 0.1-20 mg/kg of body weight, per day. Guidelines for determining particularly preferred dosage ranges within said ranges can be found in literature for treating specific conditions with specific anti-estrogenic agents of known activity. In a given case, a clinician of ordinary skill in the art can determine the optimum dosage ranges by conventional and routine experimentation. 
     Capsules, pills, tablets, dragees, etc. are suitable for oral administration. Besides the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle such as, for example, starch sugar, sorbitol, gelatin, lubricant, silicic, acid, talc, etc. The individual dosage units for oral application can contain, for example, 10 to 100 mg of the active ingredient. 
     For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils, with or with addition of a solubilizer, surfactant, or suspending or emulsifying agent, can be used. For example, olive, peanut, cottonseed, soybean, castor and sesame oils can be used. 
     The compounds can also be used in the form of a depot injection or an implantation preparation, which can be formulated so that a delayed active ingredient release is made possible. 
     Production of Starting Materials 
     The starting products of general Formula IIa or IIb to be used for the production of the compounds according to the invention of general Formula I are obtained either by: 
     (a) N-alkylation of the corresponding 1H-2-phenylindole compound X with the corresponding α,Ω-dibromoalkane Br--(CH 2 )--Br and subsequent exchange of the omega-BR atom with the NR 4  R 5  group, or 
     (b) reaction of the corresponding 1H-2-phenylindole compound X--after deprotonation--with the corresponding omega-bromoalkylcarbonamide ##STR10## the latter compounds are easily available by reaction of the corresponding omega-bromocarboxylic acid chloride ##STR11## with an excess of amine HNR 4  R 5 . 
     A1. General Directions for N-alkylation 
     1.44 g (0.06 mol) of sodium is dissolved at -70° in 200 ml of liquid ammonia. After disappearance of the blue coloring, a solution consisting of 0.035 mol of the corresponding 1H-2-phenylindole compound X (J.Med.Chem. 1984, 24, 1439) in 100 ml of tetrahydrofuran is added to this solution. After 30 minutes stirring time, a solution of 0.042 mol of alpha,omega-dibromoalkane Br--(CH 2 ) n  --Br dissolved in 20 ml of tetrahydrofuran is slowly distilled in the reaction mixture. It is stirred for 30 minutes more, and the cooling bath is removed. After evaporation of the ammonia, the remaining residue is mixed with water and extracted with ether. After separation of the phases, the organic solution is dried and concentrated by evaporation in a vacuum, and the remaining residue is recrystallized from ethanol or purified by column chromatography. 
     The N-alkyl compounds Ya to Ye thus produced are summarized in Table 7. 
     
                                           TABLE 7                                 
__________________________________________________________________________
N-Alkyl Compounds Ya to Ye by Alkylation of                               
Corresponding 1H-2-phenylindole Compounds X                               
              1H-2-Phenyl-                                                
              indole X   Br(--CH.sub.2).sub.n Br                          
                                 Melt.                                    
N-Alkyl Compound Y                                                        
              R.sub.3                                                     
                 R.sub.6                                                  
                     R.sub.7                                              
                         n       point                                    
__________________________________________________________________________
Ya 5-methoxy-2-(4-methoxy-                                                
              CH.sub.3                                                    
                 OCH.sub.3                                                
                     OCH.sub.3                                            
                         4       59-60                                    
phenyl)-3-methyl-1-                                                       
(4-bromobutyl)-indole                                                     
Yb 5-methoxy-2-(4-methoxy-                                                
              CH.sub.3                                                    
                 OCH.sub.3                                                
                     OCH.sub.3                                            
                         6       60                                       
phenyl)-3-methyl-1-(6-                                                    
bromohexyl)-indole                                                        
Yc 5-methoxy-2-(4-methoxy-                                                
              H  OCH.sub.3                                                
                     OCH.sub.3                                            
                         6       82*                                      
phenyl)-1-(-bromohexyl)-                                                  
indole                                                                    
Yd 5-methoxy-2-(4-methoxy-                                                
              CH.sub.3                                                    
                 OCH.sub.3                                                
                     OCH.sub.3                                            
                         8       oil                                      
phenyl)-3-methyl-1-(8-bromo-                                              
octyl)-indole                                                             
Ye 2-(4-methoxyphenyl)-3-                                                 
              CH.sub.3                                                    
                 H   OCH.sub.3                                            
                         6       oil                                      
methyl-1-(6-bromohexyl)-                                                  
indole                                                                    
__________________________________________________________________________
 *uncertain                                                               
 
    
     A2. General Directions for Preparation of the Compounds of General Formula IIa by Exchange of the Omega-Bromine Atom in the Alkyl Side Chain 
     (a) Reaction with a Cyclic Amine 
     A solution of 3.0 mmol of the corresponding omega-bromoalkylindole Y is heated in 100-150 ml of the cyclic amine for 4 hours to 120° C. After cooling to room temperature, it is shaken out with dichloromethane and water, the combined organic phases are on magnesium sulfate, and the solvent is distilled off. The raw products accumulating as brown oil are chromatographed on silica gel with methanol or methanol/triethylamine (1:1 to 1:3). 
     (b) Reaction with Phthalimide-Potassium/Hydrazine 
     8.0 mmol of 1-(omega-bromoalkyl)-indole compound Y and 8.8 mmol of phthalimide/potassium are refluxed in 100 ml of anhydrous dimethylformamide for 2 hours. After cooling, it is shaken out with dichloromethane and water. Then it is dried on sodium sulfate, and the solvent is distilled off. The residue is chromatographed on silica gel with dichloromethane/ethyl acetate (10:1). For release of the amine, it is taken up in 50 ml of ethanol (99 percent) and mixed with hydrazine hydrate in 20 ml of ethanol. It is refluxed for 2 hours; after cooling, is acidified (pH 2-3) with 40 ml of 2 n hydrochloric acid; and the precipitate is suctioned off. After distilling off of the solvent, it is adjusted to be alkaline (pH 8-9) with 40 ml of 2 n sodium hydroxide solution and extracted three times with 50 ml of ethyl acetate each. Then it is dried on sodium sulfate and chromatographed on silica gel with dichloroethane/trimethylamine (5:1). 
     (c) Reaction with an Aliphatic Amine 
     7.0 mmol of 1-(omega-bromoalkyl)-indole compound Y is dissolved in 30 ml of ethanol (99 percent), mixed with 40 ml of 40 percent aqueous solution of the aliphatic amine, and refluxed for 3 hours. After cooling, the ethanol is mostly removed, and the residue is taken up in 100 ml of dichloromethane and extracted with 100 ml of water. Then the organic phase is dried on magnesium sulfate, and the solvent is distilled off. The residue is chromatographed on silica gel with methanol. 
     Compounds IIa, produced according to directions A2.(a), A2.(b), and A2.(c) are set forth in Table 8. 
     
                                           TABLE 8                                 
__________________________________________________________________________
Compounds of general formula IIa from                                     
N-(omega-bromoalkyl)indoles Y                                             
                     N-(ω-bromo-                                    
                             Amine        Appear- Yield                   
Compound of general formula IIa                                           
                     alkyl) indole Y                                      
                             HNR.sub.4 R.sub.5                            
                                     Direction                            
                                          ance    (%)                     
__________________________________________________________________________
IIa 1                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Ya      Pyrrolidine                                  
                                     A2a  colorless                       
                                                  51                      
    methyl-1-[4-pyrrolidino-butyl]-       crystals                        
    indole                                mp 59-60° C.             
IIa 2                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yb      Hydrazine                                    
                                     A2b  pale yellow oil                 
                                                  ?                       
    methyl-1-[6-aminohexyl]-indole                                        
IIa 3                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yb      Methylamine                                  
                                     A2c  pale yellow oil                 
                                                  84                      
    methyl-1-[6-methylaminohexyl]-                                        
    indole                                                                
IIa 4                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yb      Dimethylamine                                
                                     A2c  pale yellow oil                 
                                                  41                      
    methyl-1-[6-dimethylaminohexyl]-                                      
    indole                                                                
IIa 5                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-                                        
                     Yc      Pyrrolidine                                  
                                     A2a  pale yellow oil                 
                                                  77                      
    1-[6-pyrrolidinohexyl]-                                               
    indole                                                                
IIa 6                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yb      Pyrrolidine                                  
                                     A2a  yellow oil                      
                                                  90                      
    methyl-1-[6-pyrrolidinohexyl]-                                        
    indole                                                                
IIa 7                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-                                        
                     Yc      Piperidine                                   
                                     A2a  pale yellow oil                 
                                                  90                      
    1-[6-piperidino-hexyl]-                                               
    indole                                                                
IIa 8                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yb      Piperidine                                   
                                     A2a  pale yellow oil                 
                                                  89                      
    methyl-1-[6-piperidino-hexyl]-indole                                  
IIa 9                                                                     
    5-Methoxy-2-(4-methoxyphenyl)-3-                                      
                     Yd      Pyrrolidine                                  
                                     A2a  yellow oil                      
                                                  65                      
    methyl-1-[8-pyrrolidino-octyl]-                                       
    indole                                                                
IIa 13                                                                    
    2-(4-Methoxyphenyl)-3-methyl-1-                                       
                     Ye      Pyrrolidine                                  
                                     A2a  pale yellow oil                 
                                                  75                      
    [6-pyrrolidino-hexyl]-indole                                          
__________________________________________________________________________
 
    
     B. General Directions for Production of the Compounds of General Formula IIb by Reaction of 1H-2-Phenylindoles X With Omega-Bromoalkylcarbonamides ##STR12## 
     In a reaction flask, 20.0 mmol of NaH in paraffin under nitrogen is freed of the paraffin by multiple washing with ether and mixed with 20 ml of dry dimethylacetamide. A solution of 14 mmol of 1H-2-phenylindole X in 80 ml of dry dimethylacetamide is instilled into this mixture under cooling with ice. After 30 minutes of stirring under ice cooling, a solution of 15 mmol of omega-bromoalkylcarbonamide in 60 ml of dry dimethylacetamide is instilled. After 2 hours of stirring at room temperature, the NaH excess is carefully destroyed with water. The reaction mixture is extracted several times with ethyl acetate. The combined organic phases are washed with water, dried on Na 2  SO 4 , and freed of solvent. The products are purified by column chromatography. 
     Compounds IIb, produced according to the above directions, are set forth in Table 9. 
     
                                           TABLE 9                                 
__________________________________________________________________________
Compounds of general formula IIb from 1-H-phenylindoles X                 
                    1H-2-Phenylindol X                                    
                               ω-Bromoalkyl-                        
                                         Appearance/                      
Compounds of general formula IIb                                          
                    R.sub.3                                               
                       R.sub.6                                            
                           R.sub.7                                        
                               carbonamide                                
                                         melting point                    
__________________________________________________________________________
IIb 16                                                                    
    5-Methoxy-2-(4-methoxyphenyl)-                                        
                    CH.sub.3                                              
                       OCH.sub.3                                          
                           OCH.sub.3                                      
                               6-bromohexanoyl-                           
                                         yellow resin                     
    3-methyl-1-(6-pyrrolidino- pyrrolidine                                
    carbonylpentyl)-indole                                                
IIb 17                                                                    
    5-Methoxy-2-(4-methoxyphenyl)-                                        
                    CH.sub.3                                              
                       OCH.sub.3                                          
                           OCH.sub.3                                      
                               6-bromohexanoyl-                           
                                         bright yellow                    
    3-methyl-1-(6-piperidino-  piperidine                                 
    carbonylpentyl)-indole                                                
IIb 18                                                                    
    5-Methoxy-2-(4-methoxypentyl)-                                        
                    CH.sub.3                                              
                       OCH.sub.3                                          
                           OCH.sub.3                                      
                               6-bromohexanoyl-                           
                                         bright brown                     
    3-methyl-1-(6-morpholinocarbo-                                        
                               morpholine                                 
                                         resin                            
    nylpentyl)-indole                                                     
IIb 19                                                                    
    1-(6-Diethylcarbamoylpentyl)-                                         
                    CH.sub.3                                              
                       OCH.sub.3                                          
                           OCH.sub.3                                      
                               6-bromohexamoyl-                           
                                         colorless resin                  
    5-methoxy-2-(4-methoxyphenyl)-                                        
                               diethylamine                               
    3-methylindole                                                        
IIb 20                                                                    
    1-(6-Benzylcarbamoylpentyl)-                                          
                    CH.sub.3                                              
                       OCH.sub.3                                          
                           OCH.sub.3                                      
                               M-(6-bromo-                                
                                         melting point                    
    5-methoxy-2-(4-methoxyphenyl)-                                        
                               hexanoyl)-                                 
                                         (ethanol)                        
    3-methylindole             benzyl-amine                               
                                         127-129                          
__________________________________________________________________________
 
    
     Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. 
     In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight. 
     The entire texts of all applications, patents, and publications, cited above and below, and of corresponding West German Application P 38 21 148.3, filed June 23, 1988, are hereby incorporated by reference. 
     EXAMPLES 
    
    
     Examples 1-20 
     C1. General Directions for Production of the Compounds of General Formula Ia (i.e., compounds of General Formula I, which exhibit at least one free hydroxy group) and IIb by Ether Cleavage of IIa or IIb 
     Under a nitrogen atmosphere and with ice cooling, there is dissolved 4.0 mmol of indole derivative IIa or IIb in 100 ml of anhydrous dichloromethane. It is stirred for about 10 minutes more, and 9.0 mmol (2.25 g, 0.85 ml) of boron tribromide, dissolved in 3 ml of absolute dichloromethane, is instilled. It is now stirred for 30 minutes with ice cooling and 2-3 hours at room temperature. With renewed ice cooling, 20 ml of ethyl acetate is instilled and stirred for 30 minutes at room temperature. It is shaken out at least three times with 50 ml each of ethyl acetate, 10 percent sodium bicarbonate solution, and water. The combined organic phases are dried on magnesium sulfate, and the resultant dried phases are dissolved in ethanol and then crystallized in a freezer. The colorless to yellow-brown products obtained of general Formula Ia or IIIb are suctioned off, washed several times with water, and dried in a desiccator on phosphorus pentoxide. 
     The compounds of general Formula Ia, thus produced, are shown in Table 10, and those of general Formula IIIb are shown in Table 11. 
     C2. General Directions for Esterification of Compounds of General Formula Ia 
     12.3 mmol of the compound of general Formula Ia is dissolved in 50 ml of methylene chloride, mixed with 20 ml of the corresponding acid anhydride or acid halide and 10 ml of pyridine and stirred overnight. Then it is put into 200 ml of water, extracted with methylene chloride, dried, and concentrated by evaporation in a vacuum. 
     C3. General Directions for Production of the Hydrochloride of a Compound of General Formula I 
     First, a compound of general Formula Ia, as described in C2, is esterified. The oily residue remaining after concentration by evaporation of the methylene chloride extract is dissolved in 200 ml of ether; hydrochloric acid gas is conducted through this solution for 30 minutes. The resulting precipitate is suctioned off and dried. 
     
                                           TABLE 10                                
__________________________________________________________________________
Example/                  Starting                 Mp      Yield          
Compound                                                                  
      Compound of general formula I                                       
                          Product   Directions                            
                                          Appearance                      
                                                   [°C.]           
                                                           [%]            
__________________________________________________________________________
1     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 1     C1    Beige Crystals                  
                                                   148 (Zers.)            
                                                           35             
      methyl-1-[4-pyrrolidino-butyl]-indole        (decom.)               
2     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 2     C1    Yellow crystals                 
                                                   &gt;139                   
                                                           76ers.)        
      methyl-1-[6-amino-hexyl]-indole              (decom.)               
3     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 3     C1    Yellow crystals                 
                                                   194 (Zers.)            
                                                           24             
      methyl-1-[6-methylamino-hexyl]-indole        (decom.)               
4     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 4     C1    Yellow crystals                 
                                                   189 (Zers.)            
                                                           73             
      methyl-1-[6-dimethyamino-hexyl]-             (decom.)               
      indole                                                              
5     5-Hydroxy-2-(4-hydroxyphenyl)-                                      
                          IIa 5     C1    Yellow crystals                 
                                                   109-112 50             
      1-[6-pyrrolidino-hexyl]-indole               (Zers.)                
                                                   (decom.)               
6     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 6/IIb 16                                    
                                    C1    Beige crystals                  
                                                   148-150 56             
      methyl-1-[6-pyrrolidino-hexyl]-indole        (Zers.)                
                                                   (decom.)               
7     5-Hydroxy-2-(4-hydroxyphenyl)-                                      
                          IIa 7     C1    Reddish brown                   
                                                   125-128 80             
      1-[6-piperidino-hexyl]-indole       crystals (Zers.)                
                                                   (decom.)               
8     5-Hydroxy-2-(4-hydroxyphenyl)-                                      
                          IIa 8/IIb 17                                    
                                    C1    Yellow crystals                 
                                                   102 (Zers.)            
                                                           23             
      3-methyl-1-[6-piperidino-hexyl]-indole       (decomp.)              
9     5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIa 9     C1    Yellow crystals                 
                                                   166-169 42             
      methyl-1-[8-pyrrolidino-octyl]-indole        (Zers.)                
                                                   (decomp.)              
10    5-Hydroxy-2-(4-hydroxyphenyl)-3-                                    
                          IIb 18          ?        107-110 ?              
      methyl-1-[6-morpholino-hexyl]-indole         (Zers.)                
                                                   (decomp.)              
11    1-(6-Diethylaminohexyl)-5-hydroxy-                                  
                          IIb 19    C1    bright yellow                   
                                                   ?       ?              
      2-hydroxyphenyl)-3-methyl-indole    amorphous                       
                                          powder                          
12    1-(6-Benzylaminohexyl)-5-hydroxy-                                   
                          IIb 20    C1    beige    ?       ?              
      2-(4-hydroxyphenyl)-3-methyl-indole amorphous                       
                                          powder                          
13    2-(4-Hydroxyphenyl)-3-methyl-1-[6-                                  
                          IIa 13    C1    Yellow crystals                 
                                                   ?       35             
      pyrrolidino-hexyl]-indole                                           
14    5-Acetoxy-2-(4-acetoxyphenyl)-3-                                    
                          Compound 7 +                                    
                                    C2    Yellow oil                      
                                                   --      53             
      methyl-1-[6-piperidino-hexyl]-indole                                
                          Acetic anhydride                                
15    5-Benzoyloxy-2-(4-benzoyloxyphenyl)-                                
                          Compound 7 +                                    
                                    C3    Pale yellow oil                 
                                                   --      55             
      3-methyl-1-[6-piperidino-hexyl]-indole                              
                          Benzoyl chloride                                
      Hydrochloride                                                       
__________________________________________________________________________
 
    
     
                                           TABLE 11                                
__________________________________________________________________________
                               Starting                                   
Example/compound                                                          
          Compound of general formula IIIb                                
                               product                                    
                                    Appearance                            
                                           Mp (°C.)                
__________________________________________________________________________
16        5-Hydroxy-2-(4-hydroxyphenyl)-3-methyl-                         
                               IIb 16                                     
                                    bright green                          
                                           ?                              
          1-(6-pyrrolidinocarbonylpentyl)-indole                          
                                    amorphous                             
                                    powder                                
17        5-Hydroxy-2-(4-hydroxyphenyl)-3-methyl-                         
                               IIb 17                                     
                                    orange 83-94                          
          1-(6-piperidinocarbonylpentyl)-indole                           
                                    amorphous                             
                                    powder                                
18        5-Hydroxy-2-(4-hydroxyphenyl)-3-methyl-                         
                               IIb 18                                     
                                    bright yellow                         
                                           ?                              
          1-(6-morpholinocarbonylpentyl)-indole                           
                                    amorphous                             
                                    powder                                
19        1-(6-Diethylcarbamoylpentyl)-5-hydroxy-2-                       
                               IIb 19                                     
                                    yellowish                             
                                           ?                              
          (4-hydroxyphenyl)-3-methylindole                                
                                    amorphous                             
                                    powder                                
20        1-(6-Benzylcarbamoylpentyl)-5-hydroxy-2-                        
                               IIb 20                                     
                                    ?      189-191                        
          (4-hydroxyphenyl)-3-methylindole                                
__________________________________________________________________________
 
    
     Examples 21-23 
     The following Examples 21-23 are pharmaceutical formulations of some compounds according to the invention. 
     Example 21 
     21 g of 5-hydroxy-2-(4-hydrophenyl)-1-(6-pyrrolidinohexyl]-indole and 89.0 g of lactose are homogeneously mixed and, in each case, 210 mg of this mixture is poured into resin gelatin, two-piece capsules of size 3. 
     Example 22 
     Tablets can be produced in the usual way from the following components: 
     
         ______________________________________                                    
50        mg of 5-hydroxy-2-(4-hydrophenyl)-3-                            
          methyl-1-(6-pyrrolidino-hexyl]-indole                           
200       mg of lactose                                                   
200       mg of microcrystalline cellulose                                
50        mg of magnesium stearate                                        
500       mg total weight of tablets                                      
______________________________________                                    
 
    
     Example 23 
     Tablets can be produced in the usual way from the following components: 
     
         ______________________________________                                    
10        mg of 5-hydroxy-2-(4-hydrophenyl)-3-                            
          methyl-1-(8-pyrrolidino-octyl]-indole                           
220       mg of lactose                                                   
220       mg of microcrystalline cellulose                                
50        mg of manesium stearate                                         
500       mg of total weight of tablets                                   
______________________________________                                    
 
    
     The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples. 
     From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.